The role of Bcl6 in the differentiation and function of follicular helper CD4 T cells Immunization is one of the most cost effective medical interventions. Most vaccines work through the generation of pathogen neutralizing antibodies made by B lymphocytes. However, these B cells cannot function properly without help from other immune system components. Another type of lymphocyte, the follicular T helper cell (TFH), is important for the generation of antibody producing B lymphocytes and germinal centers, yet TFH have only been recently discovered and their biology is not well understood. We have uncovered two transcription factors, Bcl6 and Blimp-1, that function as central regulators of TFH differentiation in mice (Science, 2009). Translation of these findings into humans will bridge critical gaps in our understanding of CD4 T cell lineage commitment and humoral immunity. By enhancing our knowledge of how these proteins control TFH differentiation and function in humans, we can ensure that vaccines are designed such that they utilize these cells to promote more effective immune responses. The ability to design immunizations in a more rational fashion will impact the traditional and cancer vaccine fields, and could enormously benefit the general population. Furthermore, because Bcl6 plays a crucial oncogenic role in many lymphomas, a more complete understanding of how Bcl6/Blimp1 control lineage commitment may bring about novel lymphoma therapies. Aim I of this proposal will investigate how Bcl6 regulates human TFH differentiation. Aim II will enhance our understanding of how LIF and other TFH cytokines affect TFH differentiation and function. PUBLIC HEALTH RELEVANCE: The vast majority of currently licensed vaccines protect humans by triggering the production of pathogen neutralizing antibodies. Follicular T helper cells are a critical component of this humoral immune response, and our knowledge of how they differentiate and function is limited. A better understanding of follicular T helper cell biology will allow for more rational vaccine design and novel therapeutic approaches to certain cancers and autoimmune conditions.